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BackgroundThe overall birth prevalence for congenital malformations of the central nervous system (CNS) among Europeans may be as high as 1 in 100 live births. The etiological factors remain largely unknown. The aim of this study was to detect causative copy number variations (CNVs) in fetuses of terminated pregnancies with prenatally detected isolated brain malformations.MethodsArray-based molecular karyotyping was performed in a cohort of 35 terminated fetuses with isolated CNS malformations. Identified putative disease-causing CNVs were confirmed using quantitative polymerase chain reaction or multiplex ligation-dependent probe amplification.ResultsBased on their de novo occurrence and/or their established association with congenital brain malformations, we detected five disease-causing CNVs in four fetuses involving chromosomal regions 6p25.1-6p25.3 (FOXC1), 6q27, 16p12.3, Xp22.2-Xp22.32 (MID1), and Xp22.32-Xp22.33. Furthermore, we detected a probably disease-causing CNV involving chromosomal region 3p26.3 in one fetus, and in addition, we detected 12 CNVs in nine fetuses of unknown clinical significance. All CNVs except for two were absent in 1307 healthy in-house controls (frequency <0.0008). Each of the two CNVs present in in-house controls was present only once (frequency = 0.0008). Furthermore, our data suggests the involvement of CNTN6 and KLHL15 in the etiology of agenesis of the corpus callosum, the involvement of RASD1 and PTPRD in Dandy-Walker malformation, and the involvement of ERMARD in ventriculomegaly.ConclusionsOur study suggests that CNVs play an important role in the etiology of isolated brain malformations.

In two of 115 patients' causative CNVs were found (2%). The remaining identified rare CNVs represent candidates for further evaluation. Rare inherited CNVs may constitute modifiers of, or contributors to, multifactorial VATER/VACTERL or VATER/VACTERL-like phenotypes. Birth Defects Research 109:1063-1069, 2017. © 2017 Wiley Periodicals, Inc.

BackgroundThe bladder exstrophy-epispadias complex (BEEC) represents the severe end of the congenital uro-rectal malformation spectrum. Initial studies have implicated rare copy number variations (CNVs), including recurrent duplications of chromosomal region 22q11.21, in BEEC etiology.MethodsTo detect further CNVs, array analysis was performed in 169 BEEC patients. Prior to inclusion, 22q11.21 duplications were excluded using multiplex ligation-dependent probe amplification.ResultsFollowing the application of stringent filter criteria, seven rare CNVs were identified: n = 4, not present in 1307 in-house controls; n = 3, frequency of <0.002 in controls. These CNVs ranged from 1 to 6.08 Mb in size. To identify smaller CNVs, relaxed filter criteria used in the detection of previously reported BEEC associated chromosomal regions were applied. This resulted in the identification of six additional rare CNVs: n = 4, not present in 1307 in-house controls; n = 2, frequency <0.0008 in controls. These CNVs ranged from 0.03–0.08 Mb in size. For 10 of these 13 CNVs, confirmation and segregation analyses were performed (5 of maternal origin; 5 of paternal origin). Interestingly, one female with classic bladder extrophy carried a 1.18 Mb duplication of 22q11.1, a chromosomal region that is associated with cat eye syndrome.ConclusionsA number of rare CNVs were identified in BEEC patients, and these represent candidates for further evaluation. Rare inherited CNVs may constitute modifiers of, or contributors to, multifactorial BEEC phenotypes.

Branchio‑otic (BO) syndrome is a clinically and genetically heterogeneous disorder that presents with variable branchial arch and otic anomalies. Dominant mutations in the human homologues of the Drosophila eyes absent (EYA1) gene, and the Drosophila sine oculis homeobox 1 and 5 (SIX1 and SIX5, respectively) genes have been causally associated with BO syndrome. Esophageal atresia (EA), with or without tracheo‑esophageal fistula (TEF), is the most common type of malformation of the upper digestive tract. To date, its causes are poorly understood. The present study investigated a family with three affected members who all presented with classic BO associated symptoms. Notably, the index patient also presented with the most common EA/TEF subtype type 3b. Whole exome sequencing (WES) was performed in the index patient, and prioritized genetic variants and their segregation in the family were analyzed by Sanger sequencing. WES demonstrated a known disease‑causing heterozygous EYA1 splice variant in the patient, as well as his sister and mother; all of whom were affected with BO syndrome. A further GLI family zinc finger 3 (GLI3) splice variant of unknown significance, inherited from the unaffected father, was also detected in the index patient. EYA1 and GLI3 are involved in the Sonic Hedgehog transcriptional network and GLI3 seems to be involved in human foregut malformations. Therefore, one may hypothesize a digenic inheritance model involving EYA1 and GLI3, where the effect of the GLI3 variant observed here only emerges in the background of the EYA1 defect.